The tumor suppressor PP2A Aβ regulates the RaIA GTPase
The tumor suppressor PP2A Aβ regulates the RaIA GTPase
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DOI：
10.1016/j.cell.2007.03.047
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发表时间：
2007-06-01
期刊：
影响因子：
64.5
通讯作者：
Hahn, William C.
中科院分区：
文献类型：
--
作者：
Sablina, Anna A.;Chen, Wen;Hahn, William C.
丝氨酸-苏氨酸蛋白磷酸酶2A（PP 2A）是一个异源三聚体酶家族，调节许多信号传导途径。PP 2A A β亚基的双等位基因突变发生在几种类型的人类肿瘤中;然而，这些癌症相关的PP 2A A β突变在细胞转化中的功能后果仍然不确定。在这里，我们表明，抑制PP 2A A β表达允许永生化的人类细胞达到致瘤状态。癌症相关的A β突变体不能逆转由PP 2A A β抑制诱导的肿瘤发生表型，表明这些突变体作为无效等位基因起作用。野生型PP 2A A β而不是癌症衍生的A β突变体与小GTdR RalA形成复合物。含有PP 2A A β的复合物在Ser 183和Ser 194处使RalA去磷酸化，使RalA失活并消除其转化功能。这些观察结果将PP 2A A β鉴定为肿瘤抑制基因，其通过调节RalA的功能来转化永生化的人类细胞。
The serine-threonine protein phosphatase 2A (PP2A) is a heterotrimeric enzyme family that regulates numerous signaling pathways. Biallelic mutations of the structural PP2A A beta subunit occur in several types of human tumors; however, the functional consequences of these cancer-associated PP2A A beta mutations in cell transformation remain undefined. Here we show that suppression of PP2A A beta expression permits immortalized human cells to achieve a tumorigenic state. Cancer-associated A beta mutants fail to reverse tumorigenic phenotype induced by PP2A A beta suppression, indicating that these mutants function as null alleles. Wild-type PP2A A beta but not cancer-derived A beta mutants form a complex with the small GTPase RalA. PP2A A beta-containing complexes dephosphorylate RalA at Ser183 and Ser194, inactivating RalA and abolishing its transforming function. These observations identify PP2A A beta as a tumor suppressor gene that transforms immortalized human cells by regulating the function of RalA.